Formation of the arterial system is a complex series of steps that is, as yet, poorly understood. The process is largely driven by vascular endothelial growth factor (VEGF) and results in formation of new arteries during embryonic development and in adult tissues. In the previous funding cycle we have uncovered novel regulatory steps that appear to play central roles in regulation of arterial growth and branching. The current proposal is aimed at further our understanding of these events and beginning development of novel therapeutic strategies that can help millions of people with ischemic cardiovascular diseases. In particular, we propose to explore the role of a novel control point that affects two major signaling input to endothelial cells- the survival/vessel maintenance signal (Akt/eNOS) and the vessel growth signal (ERK). A detailed understanding of how this regulation is accomplished would go a long way to developing drugs that could [promote growth of new arteries. In addition, we propose to explore another novel aspect of VEGF signaling discovered by our lab- spatial control of VEGF receptor 2 (VEGFR2) signaling. These studies will explore where in the cell VEGFR2 signals, what controls its trafficking and how that process is regulated. Finally, with this knowledge in hand, we will explore how elevated cholesterol levels impair VEGF signaling and what steps can be taken to overcome that. Taken together, this is a comprehensive program aimed at further our understanding of a key biological process, arteriogenesis, that may result in development of new therapeutic approaches to treatment of coronary and peripheral;arterial diseases. PUBLIC HEALTH RELEVANCE: The discovery of a signaling cascade controlling growth of new arteries will provide new insights and tools into developing new therapeutic strategies for treatment of atherosclerotic cardiovascular diseases including coronary, cerebral and peripheral vascular diseases.